Hypertension may be related not only to the action to vasoconstrictors, but also to the attenuation or absence of vasodilators. Although kallidin and bradykinin (B2) agonists are potent hypotensive peptides, it is unlikely that this system plays a role in modulating systemic blood pressure since B2 kinins are rapidly inactivated by plasma and vascular converting enzyme. However, recent discoveries regarding des(ARG)kinins(B1 agonists) suggest that this system may mediate systemic blood pressure, particularly in some forms of hypertension. The significance of the present study is that it will investigate, on a systematic basis, how arachidonic acid metabolites mediate the vasodilatory effects of des(Arg)kinins, and how such effects may modulate local blood flow under normal conditions and systemic blood pressure in hypertension. Further, these studies will identify the principal enzymatic mechanisms operative in controlling the endogenous levels of B1 Kinins, particularly in the critical micro-environment of vascular, cell surface receptors. Biochemical studies will be conducted at the subcellular, cellular and vascular levels using purified vascular plasma membrane, cultured endothelium and smooth muscle and isolated microvasculature. Analysis will include identification of B1-stimulated arachidonic acid metabolites, enzymatic and immunologic identification of des(Arg)kinin forming, converting and degrading enzymes (i.e., kallikrein, CPN, AmM and/or CPP), TLC and HPLC analysis of peptide metabolism and immunologic analysis of the relationship of the vascular and circulating forms of identified enzymes. Physiological and pharmacological studies will be conducted at the vascular and at in vivo levels to determine the role of B1 kinins in both normal and stressed (LPS, hypertension) conditions. Further, once the factors and enzymes determining the activity of the B1 kinin system have been established, experiments will be undertaken to determine whether stimulation of this endogenous vasodilatory system is (or can become) a compensatory mechanism in hypertension. Alternatively, specific enzyme inhibitors will be synthesized (which inhibit B1 kinin-degrading enzymes) to determine whether potentiation of endogenous B1 kinins is associated with significant decreases in systemic blood pressure. The concept of this new B1 kinin system is a promising approach to understanding the role of circulating vasodilators in cardiovascular diseases such as hypertension and stroke.